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Despite the observed decrease in liver fat associated with metabolic-associated fatty liver disease (MAFLD) in mice following fecal microbiota transplantation, the clinical effects and underlying mechanisms of washed microbiota transplantation (WMT), a refined method of fecal microbiota transplantation, for the treatment of MAFLD remain unclear. In this study, both patients and mice with MAFLD exhibit an altered gut microbiota composition. WMT increases the levels of beneficial bacteria, decreases the abundance of pathogenic bacteria, and reduces hepatic steatosis in MAFLD-affected patients and mice. Downregulation of the liver-homing chemokine receptor CXCR6 on ILC3s results in an atypical distribution of ILC3s in patients and mice with MAFLD, characterized by a significant reduction in ILC3s in the liver and an increase in ILC3s outside the liver. Moreover, disease severity is negatively correlated with the proportion of hepatic ILC3s. These hepatic ILC3s demonstrate a mitigating effect on hepatic steatosis through the release of IL-22. Mechanistically, WMT upregulates CXCR6 expression on ILC3s, thereby facilitating their migration to the liver of MAFLD mice via the CXCL16/CXCR6 axis, ultimately contributing to the amelioration of MAFLD. Overall, these findings highlight that WMT and targeting of liver-homing ILC3s could be promising strategies for the treatment of MAFLD.

Background and Aims: Liver stiffness measurement (LSM) by transient elastography (TE) has been assessed for the evaluation of clinically relevant outcomes in patients with chronic liver diseases (CLDs) while with variable results. This systematic review and meta-analysis aims to investigate the relationship between baseline LSM by TE and the development of clinically relevant outcomes., Methods: The systematic review identified eligible cohorts reporting the association between baseline LSM by TE and risk of hepatic carcinoma (HCC), hepatic decompensation (HD), all-cause and/or liver-related mortality and liver-related events (LREs) in CLD patients. Summary relative risks (RRs) with 95% confidence intervals (CIs) were estimated using a random-effect model. The dose-response association was evaluated by generalized least squares trend (Glst) estimation and restricted cubic splines. Commands of GLST, MKSPLINE, MVMETA were applied for statistical analysis., Results: 62 cohort studies were finally included, reporting on 43,817 participants. For one kPa (kilopascal) increment in baseline liver stiffness (LS), the pooled RR (95% CI) was 1.08 (1.05-1.11) for HCC, 1.08 (1.06-1.11) for all-cause mortality, 1.11 (1.05-1.17) for liver-related mortality, 1.08 (1.06-1.10) for HD and 1.07 (1.04-1.09) for LREs. Furthermore, the nonlinear dose-response analysis indicated that the significant increase in the risk of corresponding clinically relevant outcomes turned to a stable increase or a slight decrease with increasing baseline LS changing primarily in the magnitude of effect rather than the direction., Conclusions: The dose-response meta-analysis presents a combination between the levels of baseline LS and RRs for each clinically relevant outcome. TE, which is noninvasive, might be a novel strategy for risk stratification and identification of patients at high risk of developing these outcomes.

The correlation between improvement in longitudinal liver stiffness and fibrosis regression has not been properly evaluated during long-term antiviral therapy in chronic hepatitis B (CHB) patients. In this study, liver stiffness was serially performed by FibroScan ® every 26 weeks in a prospective cohort of CHB patients receiving entecavir. Results were compared with liver biopsies at baseline and week 78. A total of 120 treatment-naïve CHB patients were analyzed, in which 54 (45%) patients had fibrosis regression at 78 weeks of antiviral therapy. Liver stiffness measurement presented as a rapid-to-slow decline pattern and decreased more significantly in patients with fibrosis regression than those without improvement in fibrosis at week 78 (- 46.4 vs. - 28.6%, P < 0.001). Multivariate analysis revealed that percentage decline of 52-week and 78-week liver stiffness from baseline was independent predictive factors for fibrosis regression (OR = 46.6, P < 0.001; OR = 17.8, P = 0.002, respectively). Moreover, percentage decline of 78-week liver stiffness was moderately predictive of fibrosis regression (AUROC = 0.694, P < 0.001), while the optimal cutoff values were different between non-cirrhosis and cirrhosis patients (38 vs. 45%). Fibrosis regression could be predicted with a high positive predictive value (96%) in non-cirrhosis patients and could be excluded with a high negative predictive value (94%) in cirrhosis patients. In conclusion, serial liver stiffness measurement could be applied for longitudinal monitoring of fibrosis status in CHB patients. Continuous decline of liver stiffness after effective antiviral treatment could partially reflect fibrosis regression at an optimal cutoff value.

Background: Acoustic radiation force impulse (ARFI) imaging measures liver stiffness (LS), which significantly correlates with the stage of liver fibrosis in treatment-naive patients with chronic hepatitis B (CHB)., Aim: We aimed to prospectively assess the clinical usefulness of ARFI during long-term antiviral therapy in CHB., Method: Seventy-one CHB patients were consecutively recruited and paired liver biopsies were performed in 27 patients. LS was assessed by ARFI semiannually during entecavir therapy., Results: LS gradually decreased with treatment and continued to decrease after normalization of alanine aminotransaminase. Overall, 97.2% patients achieved improvement of LS, whereas 19.7% patients had more than 30% reduction in LS values between baseline and week 104. Multivariate linear regression analysis showed that the degree of LS reduction significantly correlated with the baseline levels of LS value, platelet and cholinesterase. In the 27 patients who underwent paired liver biopsies, LS significantly correlated with stage of fibrosis and inflammatory grade at baseline. LS values decreased more significantly in patients with fibrosis regression than those with static histological fibrosis., Conclusion: In CHB patients, LS assessed by ARFI was gradually reduced during antiviral therapy. Longitudinal monitoring of LS may be a promising noninvasive assessment of fibrosis regression during long-term antiviral therapy in CHB. Further large sample studies are needed., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Innate lymphoid cells (ILCs) are defined as a distinct arm of innate immunity. According to their profile of secreted cytokines and lineage-specific transcriptional factors, ILCs can be categorized into the following three groups: group 1 ILCs (including natural killer (NK) cells and ILC1s) are dependent on T-bet and can produce interferon-γ; group 2 ILCs (ILC2s) are dependent on GATA3 and can produce type 2 cytokines, including interleukin (IL)-5 and IL-13; and, group 3 ILCs (including lymphoid tissue-like cells and ILC3s) are dependent on RORγt and can produce IL-22 and IL-17. Collaborative with adaptive immunity, ILCs are highly reactive innate effectors that promptly orchestrate immunity, inflammation and tissue repair. Dysregulation of ILCs might result in inflammatory disorders. Evidence regarding the function of intrahepatic ILCs is emerging from longitudinal studies of inflammatory liver diseases wherein they exert both physiological and pathological functions, including immune homeostasis, defenses and surveillance. Their overall effect on the liver depends on the balance of their proinflammatory and antiinflammatory populations, specific microenvironment and stages of immune responses. Here, we review the current data about ILCs in chronic liver disease progression, to reveal their roles in different stages as well as to discuss their therapeutic potency as intervention targets., Competing Interests: Conflict-of-interest statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Non-specific immune responses to antigens have been demonstrated as being enhanced during chronic hepatitis B virus (HBV) infection. Here, we evaluated the role of interleukin-10 (IL-10)-producing regulatory B-cells (Bregs) in the pathogenesis of HBV-related liver fibrosis (HBV-LF) and assessed their immunoregulatory effects. Sixty-seven patients diagnosed with chronic hepatitis B (CHB) were enrolled in this study. Numbers and frequencies of peripheral B-cells (memory CD19(+)CD24(hi)CD27(+) cells, immature/transitional CD19(+)CD24(hi)CD38(hi) cells, mature CD19(+)CD24(int)CD38(int) cells) were tested and analysed. Flow cytometry-sorted CD4(+)T cells were cultured with autologous Bregs to elucidate the effects of Bregs on CD4(+)T cells, including effector T and regulatory T-cells (Tregs). The potential immunoregulatory mechanism of Bregs was also investigated. The numbers of total B-cells and Bregs were enriched in CHB patients. The frequency of Bregs was negatively correlated with elevated alanine aminotransferase (ALT) and histological inflammation grades (G), but positively correlated with advanced histological fibrosis stages (S) and enhanced HBV replication. The phenotype of Bregs was predominantly characterized as CD19(+)CD24(hi)CD38(hi) In co-culture with Bregs, CD4(+)CD25(-)T cells from CHB patients produced less interferon-γ (IFN-γ) and IL-17 but more IL-4 than CD4(+)CD25(-)T cells alone, whereas their conversions into Tregs and IL-10(+)T cells were enhanced. In addition, Breg depletion in CHB samples dramatically decreased Treg numbers and expression of cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), IL-10 and transforming growth factor-β (TGF-β). Moreover, the observed regulatory effect was partly dependent on IL-10 release and cell-to-cell contact. Elevated Bregs can suppress effector T but enhance Treg functions, which might influence immune tolerance in chronic HBV infection., (© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.)

Background: Indoles, including indole-3-carbinol (I3C) and its derivatives, are the products of glucosinolate hydrolysis catalyzed by the enzyme myrosinase. Under acidic conditions, I3C polymerizes into 3, 3- diindolylmethane (DIM), [2-(indol-3-ylmethyl)-indol-3-yl]indol-3-ylmethane (LTr1), 1-(3-hydroxymethyl)- indolyl-3-indolylmethane (HI-IM) and indolo[3,2b]carbazole (ICZ). Recently, I3C and its dimer DIM have shown pleiotropic protective effects on chronic liver injuries, including viral hepatitis, hepatic steatosis, hepatic cirrhosis, hepatocellular carcinoma, and so on., Methods: We reviewed the published papers about the pharmacokinetics of I3C and its derivatives in vitro and in vivo, and summarized their multiple protective roles in the processes of chronic liver diseases., Results: Indoles not only regulate transcriptional factors and their respective signaling pathways, but also relieve oxidative stress and inhibit the synthesis of DNA to influence the activation, proliferation and apoptosis of target cells. Moreover, indoles modulate the enzymes that are relevant to hepatitis viral replication, lipogenesis, and the metabolism of ethanol and some hepatotoxic substances to protect the liver. Currently, the immunomodulatory biofunction of indoles contributes to improving non-alcoholic steatohepatitis. In addition, indoles also function as the inhibitors of pro-inflammatory cytokines and chemokines to reduce microbial-induced liver injures., Conclusion: Indoles, especially I3C and DIM as phytochemicals, exert anti-fibrosis, anti-tumor, anti-oxidant, immunomodulatory, detoxification and anti-inflammation effects on hepatic protection through pleiotropic mechanism.